This Mentored Patient-Oriented Research Career Development application will provide for a structured environment with expert mentorship that will enable Dr. Michael Cohen-Wolkowiez to develop as an independent clinical researcher. Although antibiotics are the most commonly used medications in hospitalized infants, dosing for infants is often extrapolated from data obtained in older children and adults. Piperacillin/tazobactam and metronidazole are two antimicrobials commonly used in the nursery for which few pharmacokinetic data are available in premature infants. Dr. Cohen-Wolkowiez will use an integrative approach to investigate the pharmacokinetics and pharmacodynamics of these two agents in premature infants. This approach will include: development of a multiplex antimicrobial assay to measure drug concentrations of five antimicrobials in one ultra-low-volume infant plasma sample; application of sparse sampling methodologies; advanced population PK/PD modeling; and use of clinical opportunities to collect samples. This application will capitalize on unique opportunities provided by the Pediatric Pharmacology Research Unit-funded trial, Antimicrobial PK in High-Risk Infants (PI: Benjamin). Dr. Cohen-Wolkowiez will also have access to the resources of the Duke Clinical Research Institute and the Eshelman School of Pharmacy at UNC (Kashuba, Pollack). The mentorship team assembled is uniquely qualified, and strengths include extensive clinical research experience; internationally recognized thought leadership in trial design, research methods, pharmacology, and PK/PD modeling; and a successful history of mentorship of junior faculty. Dr. Cohen-Wolkowiez's long-term goal is to advance public health by improving antibiotic safety and dosing in infants. This K23 application will provide him with the opportunity to develop a multiplex drug assay and to master PK/PD modeling and simulation techniques in addition to refining clinical trial methodologies to maximize information gained from the limited samples available in this vulnerable population. These skills will be developed through a combination of formal didactic training in pharmacology and biostatics, as well as through mentoring from nationally recognized experts in clinical trials and pediatric pharmacology. PUBLIC HEALTH RELEVANCE: Relevance Statement Invasive infections in premature infants are common and often fatal. Therefore, physicians commonly prescribe antimicrobial agents to treat suspected or confirmed infections in this population. Appropriate dosing of most antimicrobial agents in infants is unknown and information obtained from older patients often has failed to accurately predict newborn drug disposition. This application will use a novel approach to investigate the pharmacokinetics and pharmacodynamics of antimicrobial agents commonly used in infants, using an ultra-low volume multiplex assay, scavenge sampling methodologies, and advanced PK-PD modeling.